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Pharmacogenetic Phenotypes: Alterations in Pharmacokinetics, Drug Targets and Biologic Milieu01:29

Pharmacogenetic Phenotypes: Alterations in Pharmacokinetics, Drug Targets and Biologic Milieu

Genetic variations significantly influence drug response through pharmacokinetics, receptor interactions, and biologic milieu modifications. Pharmacokinetic alterations impact drug metabolism and clearance, affecting efficacy and toxicity. Variants in drug-metabolizing enzymes, such as CYP2C9 and CYP2C19, alter drug activation and elimination. For example, CYP2C9 loss-of-function variants require lower warfarin doses to prevent excessive bleeding, while CYP2C19 variants reduce clopidogrel...
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The human genome is over 99.9% identical between individuals, yet genetic differences exist at millions of bases. The human genome contains approximately 3 million variant positions per individual, many of which are heterozygous, contributing to genetic diversity and individual traits. Genetic variations include single-nucleotide polymorphisms (SNPs), insertions, deletions, and copy number variations (CNVs).SNPs, the most common variation, involve single-base changes in DNA. These can be...
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Mutations01:35

Mutations

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Updated: Jul 10, 2026

Modified Yeast-Two-Hybrid System to Identify Proteins Interacting with the Growth Factor Progranulin
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Published on: January 17, 2012

Prominent phenotypic variability associated with mutations in Progranulin.

Brendan J Kelley1, Wael Haidar, Bradley F Boeve

  • 1Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA.

Neurobiology of Aging
|October 24, 2007
PubMed
Summary

Progranulin (PGRN) gene mutations cause frontotemporal dementia (FTD) with varied symptoms and onset ages. These mutations lead to diverse neurological conditions, including FTD with parkinsonism, highlighting significant clinical variability.

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Area of Science:

  • Neuroscience
  • Genetics
  • Neuropathology

Background:

  • Mutations in the progranulin (PGRN) gene are a known cause of frontotemporal dementia (FTD) and related parkinsonian disorders.
  • Phenotypic variability in PGRN-associated neurodegenerative diseases presents diagnostic and research challenges.

Purpose of the Study:

  • To characterize the phenotypic variability within and among kindreds with progranulin (PGRN) mutations.
  • To correlate genetic findings with clinical diagnoses, neuroimaging, and neuropathologic features.

Main Methods:

  • Retrospective review of clinical, genetic, neuroimaging, and neuropathologic data from eight kindreds with PGRN mutations.
  • Analysis of age of onset, disease duration, clinical diagnoses, and brain imaging findings.

Main Results:

  • Significant variability in age of onset (49–88 years) and disease duration (1–14 years) was observed.
  • Clinical diagnoses spanned frontotemporal dementia (FTD), primary progressive aphasia, FTD with parkinsonism, and other neurodegenerative syndromes.
  • Neuropathologic examination revealed frontotemporal lobar degeneration with ubiquitin-positive inclusions in all cases.
  • Some kindreds demonstrated consistent lateralized cerebral hemispheric atrophy (e.g., right or left) across affected individuals.

Conclusions:

  • Progranulin (PGRN) mutations are associated with a wide spectrum of clinical phenotypes and significant variability in presentation, even within families.
  • The findings underscore the complex genetic and phenotypic landscape of PGRN-associated neurodegenerative diseases.
  • Consistent lateralized degeneration patterns in some kindreds suggest potential genotype-phenotype correlations that warrant further investigation.